Is TK2 p.Arg192= (c.576G>A) pathogenic?

TK2 p.Arg192= (c.576G>A) is classified Benign/Likely benign in TK2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.085%, amr); Associated with mitochondrial DNA depletion syndrome, myopathic form.

What condition is associated with TK2 p.Arg192= (c.576G>A)?

TK2 p.Arg192= (c.576G>A) is associated with mitochondrial DNA depletion syndrome, myopathic form (ClinVar).

How common is TK2 p.Arg192= (c.576G>A) in the general population?

TK2 p.Arg192= (c.576G>A) is ultra-rare (popmax 0.085%, amr) (gnomAD).

TK2 p.Arg192=

Q: How is Mitochondrial DNA depletion syndrome, myopathic form inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.576G>A · rs146963943 · VCV137663

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.085%, amr)

Conditions

mitochondrial DNA depletion syndrome, myopathic form

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.19	GERP 0.47, phastCons 0.096
Overall
CADD	11.58	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.085% Admixed American · 51/60,006 alleles

Filtering AF 0.0663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0598%

Overall 0.0333% 538/1,614,092 alleles · ultra-rare exomes 459/1,461,882 · genomes 79/152,210 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.2%	83
Remaining individualsnot grpmax-eligible	0.096%	1,041
Admixed Americangrpmax	0.085%	1,177
European (non-Finnish)	0.00593%	16,858
African / African-American	0.00267%	37,462

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TK2
Protein: p.Arg192=
Coding: c.576G>A
MANE Select: NM_004614
dbSNP: rs146963943
Type: single nucleotide variant
Location: chr16:66517178 (GRCh38)
Gene constraint: LOEUF 1.101 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.01
Residue 192: a UniProt-annotated variant site (in mtdps2; reduction of activity)

Full TK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial DNA depletion syndrome, myopathic form — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mitochondrial DNA depletion syndrome, myopathic form (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TK2 p.Arg192Lys Pathogenic ★★ same residue
TK2 p.Arg192Gly Likely pathogenic ★ same residue
TK2 p.Ala139Thr Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Ala139Val Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Arg104Cys Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Arg130Trp Pathogenic/Likely pathogenic ★★ same condition
TK2 p.Arg183Trp Pathogenic ★★ ⚠ same condition
TK2 p.Asn58Ser Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tk2-p-arg192 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown